Abstract We propose to initiate preclinical development of a gene therapeutic targeted to Alzheimer's Disease. The World Health Organization's and Alzheimer's Disease International's report on Dementia (2012) recognizes that the global burden of Alzheimer Disease is forecast to worsen significantly with prevalence predicted to double every 20 years. Interventions that could provide a modest delay in progression would provide a significant reduction in the high level care required later in the disease. This Phase I proposal describes an Adeno-associated viral vector-based metabolic intervention strategy to combat age-related cognitive decline in the 5xFAD model of familial Alzheimer's disease. A broad range of neurodegenerative disorders manifest abnormalities in the metabolism of the abundant amino acid derivative N-acetyl-L-aspartic acid (NAA). Fluctuations in NAA concentration within the brain are generally accepted as an index of oxidative metabolic integrity in neurons. NAA synthesis and catabolism are prominent in developmental myelination, where the deacetylation of NAA in glial cells is thought to support fatty acid synthesis. Our collaborators on this proposal have recently demonstrated the importance of the deacetylation of NAA to not only fatty acid synthesis, but to the production of ATP during myelination also. These preliminary data indicate that the catabolism of acetylated aspartate leads to the synthesis of ATP by the tricarboxylic acid (TCA) cycle in myelinating glia. Preliminary studies have demonstrated that the overexpression of the NAA deacetylating enzyme, aspartoacylase (ASPA) promotes ATP synthesis, thereby providing a means of support during periods of oxidative stress and promotion of cell survival following anoxic injury. In Phase I we will quantify the therapeutic effect in an animal model of neurodegenerative disease. Using our technology platform we will express a gene encoding an oligodendrocyte-localized catabolic enzyme in neurons to enable the liberation of free acetate from the abundant amino acid derivative N- acetylaspartate. Assessment will be made of biochemical, histopathological and cognitive outcomes. In summary, the experiments described herein will address the potential of using adeno- associated viral vectors to provide a means by which metabolic intermediates of oxidative metabolism are made available to cholinergic basal forebrain neurons of transgenic mice that model -amyloid induced neurodegeneration and cognitive decline. This novel yet simple strategy may promote metabolic integrity and improved cognitive performance in a model of familial Alzheimer's disease using an established gene delivery system with proven clinical safety. If the treatment provides a significant magnitude of benefit in the established models of AD it will be advanced into Phase II testing involving dose ranging, toxicity and biodistribution studies.